This invention relates to an improved process for the preparation of substituted tetrazole derivative (s) to minimize genotoxic impurities. Specifically, the present invention discloses a process for the preparation of angiotensin-II-receptor blockers essentially free of genotoxic impurities.
BACKGROUND OF THE INVENTION
Angiotensin-II-receptor blockers (ARBs), known as sartans, are a group of pharmaceuticals that modulate the renin–angiotensin system. Their main uses are in the treatment of hypertension (high blood pressure), diabetic nephropathy (kidney damage due to diabetes) and congestive heart failure. There are ARBs that contain tetrazole moiety such as valsartan, losartan potassium, irbesartan, olmesartan medoxomil and candesartan cilexetil and other ARBs which do not contain a tetrazole skeleton such as azilsartan medoxomil potassium, telmisartan and eprosartan mesylate.
Various synthesis routes have already been reported in the literature for the synthesis of ARBs that contain a tetrazole moiety. Among them, processes for preparing tetrazole compounds from nitrile compounds are disclosed in the following, as for Losartan-potassium, US Patent No. 5,138,069 and International Publication Nos. WO 2007/020654 and WO 2007/026375. As for Valsartan, US Patent Nos. 5,965,592 and 5,399,579, and International Publication No. WO 2007/014412. As for Candesartan cilexetil, US Patent No. 5,705,517, European Patent No. 459,136, and International Publication Nos. WO 2006/015134, WO 2007/094015 and WO 2007/054965. As for Irbesartan, US Patent Nos. 5,270,317, 5,629,331 and 7,211,676, US Patent Publication No. 20090286990 and International Publication No. WO 2007/013101. As for Olmesartan medoxomil, European Patent No. 503,785.
U.S. Patent No. 5,399,578 discloses valsartan and its pharmaceutically acceptable salts, pharmaceutical compositions and their use in treating high blood pressure and cardiac insufficiency. It also discloses a process for the preparation of valsartan, which involves the condensation of N-[2'-cyanobiphenyl-4-yl-(methyl)]-(L)-valine methyl ester with valeryl chloride in the presence of triethylamine and dichloromethane, followed by flash chromatography to give the compound N-[2'-cyanobiphenyl-4-yl)methyl]-N-valeryl-(L)-valine methyl ester, which is then treated with tributyl tin azide to achieve tetrazole ring formation. The tetrazole compound so obtained is then hydrolyzed using sodium hydroxide to give valsartan after flash chromatography. The cited US patent further describes a variant of above method with use of benzyl ester. The process disclosed uses flash chromatography at various stages during the preparation of valsartan that makes the process difficult to operate and uneconomical on industrial scale.
U.S. Patent Application Publication No. 20060281801 discloses a process for the preparation of valsartan, which involves a purification method for the removal of organotin impurity form benzyl valsartan. The purification process for the removal of organotin impurity is very elaborate and involves subsequent purifications, which involve first crystallization of benzyl valsartan intermediate from a ternary solvent mixture and then a second crystallization from a binary solvent system to yield benzyl valsartan. As the disclosed process involves multiple crystallizations, it is very time consuming, involves use of large volume of mixed solvents during crystallization step and in-turn generates more effluent, thus the process becomes industrially uneconomical and unacceptable.
U.S. Patent Application Publication No. 20070093542 discloses a process for the preparation of valsartan containing less than about 5000 ppm residual solvent involving the use of humid air in fluidized bed drier and drying by maintaining valsartan at a temperature from 5 to 60°C under pressure of less than 30 mm Hg for a period of 1 to 5 days. The duration involved in achieving the valsartan of the desired characteristics of pharmacopoeia standards is very long for the implementation on industrial scale.
U.S. Patent Application Publication No. 20090192318 discloses a process for the preparation of valsartan, wherein the trityl protected valsartan benzyl ester intermediate is converted to its hydrochloride salt in an attempt to purify the said intermediate. The hydrochloride salt formation is carried out at specific pH and precise temperature conditions. Even a slight temperature rise or variation in pH leads to the formation of undesired impurities. Use of such stringent reaction conditions in an industrial process is not feasible in terms of ease of operation of process and also, it is difficult to control the formation of undesired impurity in such a process at large scale. The said limitations render the disclosed process infeasible and impractical on industrial scale.
U.S. Patent No. 5,138,069 filed by Dupont reported a procedure for the preparation of Losartan wherein 4`-bromomethyl-2-cyanobiphenyl is reacted with 2-n-butyl-4-chloro-5-hydroxymethyl imidazole in the presence of a base to give cyano alcohol and its regioisomer. The separation of the isomer needed column chromatography, after which the desired cyano alcohol obtained is reacted with sodium/ammonium azide in DMF for 13 days to get Losartan in 21% yield. Thus, the disclosed process suffered limitations in terms of use of complex procedures like column chromatography, which are not suitable at industrial level and very low yields which is not cost efficient.
U.S. Patent No. 5,270,317 discloses a process for the preparation of another ARB, irbesartan, wherein the process involves reaction of 2-(n-butyl)-3-[[2'-(cyano)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one either with tributyltin azide or triphenyl chloromethane in xylene at reflux. The resulting compound is subjected to elimination of the triphenylmethyl protecting group and irbesartan is isolated from ethyl acetate. Similar approach is used in J. Med. Chem., 1993, 36, 3371-3380, wherein irbesartan is isolated from dichloromethane. Due to the loss of triphenylmethyl group there is no atom economy. The reported processes are not particularly suitable for industrial application due to their inefficiency on impurity control and low yield.
U.S. Patent No. 5,616,599 discloses olmesartan medoxomil and process for its preparation, wherein the process involves reaction of an imidazole derivative with a dioxolyl compound and the resulting moiety is reacted with biphenyl methyl halide to obtain trityl olmesartan medoxomil, which is subsequently deprotected using 75% acetic acid at 60oC to obtain olmesartan medoxomil. The product so obtained contained 4-5% of olmesartan acid impurity, which needs further purification using column chromatography. The disclosed process is tedious, had inefficient control on impurity generation and had long cycle time, thus not suitable for large scale application.
U.S. Patent No. 5,196,444 discloses candesartan as candesartan cilexetil and also discloses process for its preparation. The process involves formation of 1-[[(cyclohexyloxy)carbonyl]oxy]ethyl-2-ethoxy-1-[[2'-(1H-tetrazol-5-yl) 1,1'biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate by reacting 2-ethoxy-1-[[2'-(N-triphenylmethyltetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid in DMF with cyclohexyl-1-iodoethyl carbonate, which is subjected to deprotection with a methanolic hydrochloric acid to form candesartan cilexetil. The disclosed process fails to be applicable for large scale application as it do not have efficient yield to be economical and also suffers from lesser control on impurity formation which requires additional purification processes.
Despite the progress in the manufacturing operations for ARBs and various controls applied to make the drugs acceptable for human consumption as per laid down guidelines of drug authorities’ world over, the recent alarming situation has gripped the pharmaceutical industry manufacturing the substituted tetrazole derivatives (sartans). From July 2018, several drug companies voluntarily recalled their blood pressure and heart medication drugs including valsartan, losartan and irbesartan after finding trace amount of unexpected impurities i.e nitrosamine, thus in light of probable contamination of nitrosamine impurities particularly N-nitrosodimethylamine (NMDA/NDMA) of Formula II and N-nitrosodiethylamine (NEDA/NDEA) of Formula III in sartans particularly when the manufacturing process may lead to the formation of a nitrosamine or when recycled raw materials / solvents can create unacceptable contamination or due to probable saturation of nitrosamine in environment, it becomes inevitable to identify potential cross contamination risks for drugs manufactured, to include enhanced evaluation of impurity controls and to demonstrate a capability of predicting, controlling, and preventing impurities in the drug substance and subsequently in the drug product.

Formula II Formula III
The processes disclosed in the prior art fail to provide the control of genotoxic nitrosamine impurities. Consequently, there is a need for an improved process for the preparation of substituted tetrazole derivatives, which not only overcomes the problems in the prior art processes as mentioned above, but also is simple, environment friendly, economically viable and industrially feasible for the preparation of substituted tetrazole derivatives having the desired recommended pharmacopeia quality.

OBJECT AND SUMMARY OF THE INVENTION
The principal object of the present invention is to overcome or alleviate at least one of the deficiencies of prior art and provide a useful alternative for the preparation of substituted tetrazole derivative (s) suitable for human consumption.
It is another object of the present invention to provide a simple, economic and efficient process for the preparation of substituted tetrazole derivatives essentially free of nitrosamines, wherein nitrosamine is selected from the group comprising of N-Nitrosodimethylamine, N-Nitrosodiethylamine, N-Nitrosodiisopropylamine (NDIPA/DIPNA), N-Nitrosoethylisopropylamine (EIPNA), N-Nitrosomethylethylamine (NMEA), N-Nitrosodipropylamine (NPDA), N-Nitrosodibutylamine (NBDA), N-Nitrosomethyldodecylamine, N-Nitroso-N-methyl-N-tetradecylamine, N-Nitroso-N-methyl-4-fluoroaniline, N-Nitroso-N-methyl-N-(2-phenyl) ethylamine, (4-(methyl) (nitroso) amino) butanoic acid.
DESCRIPTION OF THE INVENTION
While this specification concludes with claims particularly pointing out and distinctly claiming that, which is regarded as the invention, it is anticipated that the invention can be more readily understood through reading the following detailed description of the invention and study of the included examples.
Nitrosamines are potent carcinogens in animals and probable carcinogens in humans, particularly important are N-nitrosodimethylamine (NDMA), and N-nitrosodiethylamine (NDEA). Until recently, NDMA and NDEA were not among the impurities identified in substituted tetrazole derivative medicines and were therefore not detected by routine tests.The probable reason of formation of nitrosamine as impurities is that they can form during the production of substituted tetrazole derivatives to form a tetrazole ring when certain reaction conditions are met or due to contaminated raw material/intermediates used in the manufacturing process. Apart from this, use of recovered solvents and recovered catalysts, may pose a risk for nitrosamine formation due to the presence of secondary or tertiary amines in the solvents or catalysts after recovery and the subsequent quenching of these materials with nitrous acid to destroy residual azide without adequate removal. According to one of the possible concepts, the key step involves dimethylamine (DMA) which forms the impurity NDMA in the presence of nitrites, usually under acidic conditions. A similar step involving diethylamine (DEA) is linked to the presence of NDEA. ICH M7 recommends that these mutagenic carcinogens be controlled at or below the acceptable cancer risk level. Due to their known potent carcinogenic effects, and because it is feasible to limit these impurities by taking reasonable steps to control or eliminate their presence, the goal is to have no quantifiable nitrosamine impurities or well within the declared limits in substituted tetrazole derivatives which is safe for human consumption.
Understanding the limitations of prior art, there is a need for the development of an advantageous process for the preparation of substituted tetrazole derivatives, and the best optimized process would always have better control on the formation of nitrosamine impurity rather than the removal of such impurities by purification, since such impurities once formed are difficult to remove and their removal adds up to the cost of process, making the process inefficient in several ways.
The inventors of the present invention keenly devised the conditions through extended studies suitable for preparing substituted tetrazole derivatives essentially free of nitrosamine impurities the inventors provided a process for the preparation of substituted tetrazole derivatives involving use of suitable drying conditions. This approach have shown very efficient control on formation of nitrosamine impurities. The process developed ensures the quality of substituted tetrazole derivatives prepared in safe manner. Furthermore, the process of present invention also reduces the requirement of purifications and thereby reduces solvent consumption, operational step and the time cycle and effluent generation, making the process cost effective and environmentally efficient.
The present invention relates to a process for preparing a substituted tetrazole derivative of formula I essentially free of nitrosamines,

Formula I
wherein R represents an organic residual group, and
R represents linear or branched C1-C6-alkyl or C3-C6-cycloalkyl, each of which is optionally substituted with one or more (preferably 1 to 4) substituents selected from:
halogen; hydroxy; C1-C6-alkyl; C1-C6-alkoxy; and phenyl, pyridine, pyrimidine, imidazole, thiophene and furan, each of which is optionally substituted with one or more (preferably, 1 to 4) substituents selected from the group consisting of C1-C6-alkyl, halogen, hydroxy, nitro and C1-C6-alkoxy, or
R represents phenyl or biphenyl of the following formula:

wherein each of R1 and R2 is independently selected from the group consisting of
hydrogen; halogen; hydroxy; nitro; C1-C6-alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, hexyl); C3-C6-cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl); C1-C6-alkoxy; phenylmethyl, pyridylmethyl, pyrimidylmethyl, imidazolylmethyl, benzimidazolylmethyl, thiophenylmethyl and furanylmethyl, each of which is optionally substituted with one to four substituents selected from the group consisting of halogen, carboxy, oxo, C1-C6-alkyl, C1-C6-alkoxy, hydroxy-C1-C6-alkyl, C1-C6-alkoxycarbonyl, C1-C6-alkoxycarbonyl-C1-C6-alkyl, C3-C6-alkanediyl, di(C1-C6-alkyl)aminothiocarbonyl-C1-C6-alkyl, cilexetiloxycarbonyl and medoxomiloxycarbonyl; and amino or amino-C1-C6-alkyl, each of which is optionally substituted with one or two substituents selected from the group consisting of C1-C6-alkyl, C3-C6-cycloalkyl, C1-C6-alkylcarbonyl, carboxy-C1-C6-alkyl and C1-C6-alkoxycarbonyl-C1-C6-alkyl (for example, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, diisopropylamino, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino)
wherein the process comprises of drying compound of formula I in controlled humidity drying conditions.
In the compounds of Formula I prepared according to the present invention, some concrete structures of the substituent R are as follows:

(a) (b) (c)

(d) (e)
in structure b, R3 represents hydrogen or methyl.
in structure c, R4 represents hydrogen, methyl, ethyl or cilexetil.
in structure e, R5 represents hydrogen, methyl, ethyl or medoxomil.
According to the present invention, the controlled humidity drying condition is comprised of humidity drying conditions with relative humidity up to about 90%.
According to the present invention, the substituted tetrazole derivative of Formula I is subjected to drying to remove solvent under controlled humidity conditions, wherein the relative humidity during drying is up to about 90%. The drying method used is selected from the group comprising of vacuum drying, fluidized bed drying, freeze drying, rotary vacuum drying convection drying and the like as known in the literature. The relative humidity is controlled by using method selected from the group comprising of use of de-humidifier, desiccant dryer method and the like. The drying is carried out at temperature from about room temperature to 200?C, for 1-50 h. The temperature of dryer is increased optionally in stepwise manner, starting from lower temperature range to higher range, by keeping each range of temperature constant for about 1-20 h.
The substituted tetrazole derivative of Formula I used herein as starting material contain solvent wherein the solvent is selected from organic solvent, water and mixtures thereof used during the preparation of substituted tetrazole derivative of Formula I.
According to the embodiment of the present invention, substituted tetrazole derivative of Formula I used herein can be prepared according to the processes as disclosed in the prior art.
According to the one preferred aspect of the present invention, the substituted tetrazole derivative of Formula I, valsartan, wherein R is structure (b) and R3 is hydrogen is prepared by process comprising the steps of:
(a) reacting 2-[(2'-cyano-biphenyl-4-ylmethyl)-amino]-3-methyl-butyric acid methyl ester hydrochloride of Formula II with valeryl chloride to obtain 2-[(2'-cyano-biphenyl-4-ylmethyl)-pentanoyl-amino]-3-methyl-butyric acid methyl ester of Formula III;

Formula II Formula III
(b) reacting 2-[(2'-cyano-biphenyl-4-ylmethyl)-pentanoyl-amino]-3-methyl-butyric acid methyl ester of Formula III with metal azide in presence of trialkyl tin chloride to obtain 3-methyl-2-{pentanoyl-[2'-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amino}-butyric acid methyl ester of Formula IV;

Formula IV
(c) hydrolyzing 3-methyl-2-{pentanoyl-[2'-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amino}-butyric acid methyl ester of Formula IV to obtain valsartan.
(d) drying valsartan under controlled humidity conditions.
According to the present invention, the reaction of 2-[(2'-cyano-biphenyl-4-ylmethyl)-amino]-3-methyl-butyric acid methyl ester of Formula II with valeryl chloride is carried out to obtain compound of Formula III. The compound of formula II optionally is used as an acid addition salt, wherein the acid is selected from hydrochloric acid and the like. The reaction is carried out by first neutralizing the compound of formula II acid addition salt using a base and solvent, which is subsequently treated with valeryl chloride. The base used is selected from inorganic, organic or mixtures thereof. The inorganic base is selected from a group comprising of alkali and alkaline earth metal hydroxide, carbonate, and bicarbonate, wherein the alkali and alkaline earth metal is selected from lithium, sodium, potassium, calcium, magnesium, barium and the like. The organic base is selected from a group comprising of N,N-dimethylamine, N-ethyl-N-methyl amine, triethylamine, diisopropylethylamine, N,N-dimethylbenzylamine, N,N-diethylbenzylamine, N-methyl morpholine, dimethylaminopyridine, pyridine and the like. The solvent used herein is selected from a group comprising of halogenated solvents such as dichloromethane, ethylene dichloride, chloroform, chlorobenzene, chlorotoluene, 1,2-dichlorobenzene, 1,3-dichlorobenzene and the like; esters such as ethyl acetate, n-propyl acetate, isopropyl acetate, butyl acetate and the like; hydrocarbons such as toluene, xylene, n-hexane, n-heptane, cyclohexane and the like or mixtures thereof. In accordance with the present invention, the reaction is carried out at temperature from about -5 to 15?C, for 0.5-3 hour.
According to the present invention, the resulting compound 2-[(2'-cyano-biphenyl-4-ylmethyl)-pentanoyl-amino]-3-methyl-butyric acid methyl ester of Formula III is reacted with metal azide in the presence of trialkyl tin halide optionally in a solvent to obtain compound of Formula IV, wherein the metal azide is selected from a group comprising of alkali and alkaline earth-metal azide. The alkali and alkaline earth metal is selected from lithium, sodium, potassium, calcium, magnesium, barium and the like, preferably sodium. The trialkyl tin chloride used is selected from the group comprising of trimethyl tin chloride, triethyl tin chloride, tributyl tin chloride and the like. The solvent used herein is selected from a group comprising of halogenated solvents such as dichloromethane, ethylene dichloride, chloroform, chlorobenzene, chlorotoluene, 1,2-dichlorobenzene, 1,3-dichlorobenzene and the like; esters such as ethyl acetate, n-propyl acetate, isopropyl acetate, butyl acetate and the like; hydrocarbons such as toluene, xylene, n-hexane, n-heptane, cyclohexane and the like or mixtures thereof. In accordance with the present invention, the reaction is carried out at temperature from about 40?C to reflux temperature, for 15-30 h.
According to the present invention, the resulting compound of Formula IV is hydrolyzed in presence of a base under pressure to obtain valsartan, wherein the base is selected from a group comprising of alkali and alkaline earth metal hydroxide, carbonate, hydride and bicarbonate, wherein the alkali and alkaline earth metal is selected from lithium, sodium, potassium, calcium, magnesium, barium and the like, preferably sodium hydroxide. In accordance with the present invention, the hydrolysis is optionally carried out in the presence of a solvent. The solvent used herein is selected from a group comprising of halogenated solvents such as dichloromethane, ethylene dichloride, chloroform, chlorobenzene, chlorotoluene, 1,2-dichlorobenzene, 1,3-dichlorobenzene and the like; esters such as ethyl acetate, n-propyl acetate, isopropyl acetate, butyl acetate and the like; hydrocarbons such as toluene, xylene, n-hexane, n-heptane, cyclohexane and the like; water or mixtures thereof. In accordance with the present invention, the hydrolysis is carried under pressure ranging from 2-6 kg, preferably using an inert gas at temperature of about 0 to 15 ?C, for 25-40 h. The inert gas used is selected from the group comprising of argon, nitrogen and the like. The valsartan so obtained is purified using a suitable solvent and is filtered to get valsartan. The solvent used for crystallization is selected from the group comprising of halogenated solvents such as dichloromethane, ethylene dichloride, chloroform, chlorobenzene, and the like; esters such as ethyl acetate, n-propyl acetate, isopropyl acetate, butyl acetate and the like. The method of purification used is selected from crystallization, solvent-anti solvent precipitation, slurry washing and the like.
According to the present invention, the valsartan obtained is having solvent and need further drying under suitable drying conditions in order to qualify for desired residual solvent limits of pharmacopeia standard. The drying method used is selected from the group comprising of vacuum drying, fluidized bed drying, freeze drying, rotary vacuum drying convection drying and the like as known in the literature. The relative humidity is maintained by using method selected from the group comprising of use of de-humidifier, desiccant dryer method and the like. The drying is carried out at temperature from about room temperature to 200?C, for 1-50 h. The temperature of dryer is increased optionally in stepwise manner, starting from lower temperature range to higher range, by keeping each range of temperature constant for about 1-20 h.
The starting material 2-[(2'-cyano-biphenyl-4-ylmethyl)-amino]-3-methyl-butyric acid methyl ester is obtained according to the methods disclosed in the prior art.
According to another preferred aspect of the present invention, the substituted tetrazole derivative of Formula I, irbesartan, wherein R is structure (d) is prepared by process comprising reacting 2-(n-butyl)-3-[[2'-(cyano)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one with azide in the presence of organic base or its salt and optionally employing a solvent to obtain crude irbesartan, which is crystallized to obtain irbesartan. The irbesartan is dried to remove solvent under suitable drying conditions.
According to the present invention, the azide for reaction with 2-(n-butyl)-3-[[2'-(cyano)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one is alkali metal azide. The organic base or its salt used is selected from the group comprising of triethyl amine, diethyl amine, ethyl methyl amine and the like. The solvent used herein is selected from the group comprising aromatic or aliphatic hydrocarbons such as heptane, toluene or xylene, ketones such as methyl isobutyl ketone, esters such as n-butyl acetate, ethers such as dioxane or alcohols such as n-butanol. The crude irbesartan is further purified using solvent selected from alcohol to obtain irbesartan.
According to the present invention, the irbesartan obtained is having solvent and need further drying in order to qualify for desired residual solvent limits of pharmacopeia standard. The drying method used is selected from the group comprising of vacuum drying, fluidized bed drying, freeze drying, rotary vacuum drying convection drying and the like as known in the literature. The relative humidity is maintained by using method selected from the group comprising of use of de-humidifier, desiccant dryer method and the like. The drying is carried out at temperature from about room temperature to 200?C, for 1-50 h.
The starting material 2-(n-butyl)-3-[[2'-(cyano)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one is obtained according to the methods disclosed in the prior art.
According to yet another preferred embodiment of the present invention, the substituted tetrazole derivative of Formula I, olmesartan medoxomil, wherein R is structure (e) and R5 is medoxomil, is prepared by process comprising of reacting ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(trityl-tetrazol-5-yl)phenyl]phenyl} methylimidazole-5-carboxylate with a base in solvent to obtain 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(trityl-tetrazol-5-yl)phenyl]phenyl} methylimidazole-5-carboxylic acid salt and esterifying the corresponding salt with 4-chloromethyl-5-methyl-2-oxo-1,3-dioxolene to obtain trityl olmesartan medoxomil and deprotecting the trityl olmesartan medoxomil in solvent to olmesartan medoxomil. The olmesartan medoxomil is dried under suitable drying conditions.
According to the present invention, the reaction of ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(trityl-tetrazol-5-yl)phenyl]phenyl} methylimidazole-5-carboxylate is carried out using base and solvent to obtain 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(trityl-tetrazol-5-yl)phenyl]phenyl} methylimidazole-5-carboxylic acid salt. The base used is selected from inorganic and organic and solvent is selected from the group comprising of alcohol, ether, water and mixtures thereof.
According to the present invention, the esterification of 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(trityl-tetrazol-5-yl)phenyl]phenyl} methylimidazole-5-carboxylic acid salt with 4-chloromethyl-5-methyl-2-oxo-1,3-dioxolene is carried out in presence of base and solvent, wherein the base used is inorganic base selected from the group comprising of carbonate, bicarbonate and hydroxides of sodium metal and the solvent used is selected from the group comprising of alcohol, ether, water and mixtures thereof.
According to the present invention, the trityl olmesartan medoxomil obtained is deprotected in presence of acetonitrile as solvent and the deprotecting agent selected from the group comprising of hydrochloric acid, hydrobromic acid, sulphuric acid and the like to obtain olmesartan medoxomil.
According to the present invention, the olmesartan medoxomil so obtained is purified using a suitable solvent and is filtered to get olmesartan medoxomil. The solvent used for crystallization is selected from the group comprising of halogenated solvents such as dichloromethane, ethylene dichloride, chloroform, chlorobenzene, and the like; esters such as ethyl acetate, n-propyl acetate, isopropyl acetate, butyl acetate and the like. The method of purification used is selected from crystallization, solvent-anti solvent precipitation, slurry washing and the like. The olmesartan medoxomil obtained is having solvent and need further drying under suitable conditions in order to qualify for desired residual solvent limits of pharmacopeia standard. The drying method used is selected from the group comprising of vacuum drying, fluidized bed drying, freeze drying, rotary vacuum drying convection drying and the like as known in the literature. The relative humidity is maintained by using method selected from the group comprising of use of de-humidifier, desiccant dryer method and the like. The drying is carried out at temperature from about room temperature to 200?C, for 1-50 h.
The starting material the ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(trityl-tetrazol-5-yl)phenyl]phenyl} methylimidazole-5-carboxylate is obtained according to the methods disclosed in the prior art.
According to yet another preferred embodiment of the present invention, the substituted tetrazole derivative, losartan potassium, when R is structure (a), is obtained by reacting 2-butyl-5-chloro-1H-imidazole-4-carbaldehyde with 4'-(bromomethyl)-[1,1'-biphenyl]-2-carbonitrile to obtain 2-butyl-4-chloro-1-[(2’-cyanobiphenyl-4-yl)methyl]imidazole-5-carboxaldehyde, which is reduced using reducing agent to obtain 4'-((2-butyl-4-chloro-5-(hydroxymethyl)-1H-imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-carbonitrile. The 4'-((2-butyl-4-chloro-5-(hydroxymethyl)-1H-imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-carbonitrile is subjected to tetrazole ring formation using metal azide in presence of base or its salt and solvent to obtain (1-((2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-2-butyl-4-chloro-1H-imidazol-5-yl)methanol (losartan). The losartan base is then converted to losartan potassium using a suitable potassium ion source in presence of solvent. The losartan potassium obtained is dried under suitable dying conditions.
According to the present invention, reaction of 2-butyl-5-chloro-1H-imidazole-4-carbaldehyde with 4'-(bromomethyl)-[1,1'-biphenyl]-2-carbonitrile in presence of solvent and optionally in presence of phase transfer catalyst. The solvent used is selected from the group comprising of alcohol, ether, aliphatic hydrocarbon, aromatic hydrocarbon, water and mixtures thereof. The phase transfer catalyst used is selected from the group comprising of quaternary ammonium salts, crown ethers and phosphonium compounds. The 2-butyl-4-chloro-1-[(2’-cyanobiphenyl-4-yl)methyl]imidazole-5-carboxaldehyde obtained is reduced using suitable reducing agent to obtain 4'-((2-butyl-4-chloro-5-(hydroxymethyl)-1H-imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-carbonitrile. The reducing agent used is selected from the group comprising of lithium aluminum hydride, sodium borohydride and the like.
According to the present invention, 4'-((2-butyl-4-chloro-5-(hydroxymethyl)-1H-imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-carbonitrile is subjected to tetrazole ring formation in presence of alkali metal azide. The organic base or its salt used is selected from the group comprising of triethyl amine, diethyl amine, ethyl methyl amine and the like. The solvent used herein is selected from the group comprising aromatic or aliphatic hydrocarbons such as heptane, toluene or xylene, ketones such as methyl isobutyl ketone, esters such as n-butyl acetate, ethers such as dioxane or alcohols such as n-butanol. The losartan obtained is reacted with potassium ion source in solvent to form losartan potassium, wherein the potassium ion source is selected from the group comprising of potassium hydroxide, potassium carbonate and the like. The losartan potassium so formed is isolated using techniques known in the art such as crystallization, solvent-anti solvent technique. The losartan potassium obtained is having solvent and need further drying under suitable conditions in order to qualify for desired residual solvent limits of pharmacopeia standard. The drying method used is selected from the group comprising of vacuum drying, fluidized bed drying, freeze drying, rotary vacuum drying convection drying and the like as known in the literature. The relative humidity is maintained by using method selected from the group comprising of use of de-humidifier, desiccant dryer method and the like. The drying is carried out at temperature from about room temperature to 200?C, for 1-50 h. and is further purified dried in suitable drying conditions to remove solvent.
The starting material 2-butyl-5-chloro-1H-imidazole-4-carbaldehyde and 4'-(bromomethyl)-[1,1'-biphenyl]-2-carbonitrile are obtained according to the methods disclosed in the prior art.
According to yet another preferred embodiment of the present invention, the substituted tetrazole derivative of Formula I, candersartan ciltexetil, when R is (c) and R4, is obtained by reacting ethyl 1-((2'-cyano-[1,1'-biphenyl]-4-yl)methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylate with alkali metal azide in the presence of trialkyl tin halide optionally in a solvent followed by hydrolysis in presence of a base to obtain 1-((2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylic acid, which is further subjected to tetrazole ring protection using suitable protecting agent, preferably trityl. The protected 2-ethoxy-1-((2'-(1-trityl-1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylic acid is then reacted with cilexetil chloride in presence of base and solvent to obtain 1-(((cyclohexyloxy)carbonyl)oxy)ethyl 2-ethoxy-1-((2'-(1-trityl-1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylate, which is subjected to deprotection reaction to obtain crude candesartan cilexetil, which is crystallized to obtain candesartan cilexetil. The candesartan cilexetil obtained is dried under suitable dying conditions.
According to the present invention, the ethyl 1-((2'-cyano-[1,1'-biphenyl]-4-yl)methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylate is reacted with alkali metal azide in the presence of trialkyl tin halide optionally in a solvent followed by hydrolysis in presence of a base, to obtain 1-((2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylic acid. The base used is selected from the group comprising of alkali and alkaline earth metal, carbonate, hydride and bicarbonate. The alkali and alkaline earth metal is selected form the group compsrising of lithium, sodium, potassium, magnesium, barium and the like, preferably sodium. The trialkyl tin chloride used is selected from the group comprising of trimethyl tin chloride, triethyl tin chloride, tributyl tin chloride and the like. The solvent used herein is selected from a group comprising of halogenated solvents such as dichloromethane, ethylene dichloride, chloroform, chlorobenzene, chlorotoluene, 1,2-dichlorobenzene, 1,3-dichlorobenzene and the like; esters such as ethyl acetate, n-propyl acetate, isopropyl acetate, butyl acetate and the like; hydrocarbons such as toluene, xylene, n-hexane, n-heptane, cyclohexane and the like or mixtures thereof.
According to the present invention, 1-((2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylic acid is reacted with suitable protecting reagent in presence of base and solvent to obtain 2-ethoxy-1-((2'-(1-trityl-1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylic acid. The suitable protecting reagent used is selected from trityl chloride and the like. The base used is selected from inorganic and organic. The solvent used herein is selected from a group comprising of halogenated solvents such as dichloromethane, ethylene dichloride, chloroform, chlorobenzene, chlorotoluene, 1,2-dichlorobenzene, 1,3-dichlorobenzene and the like; esters such as ethyl acetate, n-propyl acetate, isopropyl acetate, butyl acetate and the like; hydrocarbons such as toluene, xylene, n-hexane, n-heptane, cyclohexane and the like or mixtures thereof. In accordance with the present invention, the reaction is carried out at temperature from about 15 to 40 ?C, for 0.5-5 hour.
According to the present invention, 2-ethoxy-1-((2'-(1-trityl-1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylic acid is reacted with cilexetil chloride in presence of base and solvent to obtain 1-(((cyclohexyloxy)carbonyl)oxy)ethyl 2-ethoxy-1-((2'-(1-trityl-1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylate. The base used is selected from inorganic and organic. The solvent used is selected from the group comprising of halogenated solvents such as dichloromethane, ethylene dichloride, chloroform, chlorobenzene, chlorotoluene, 1,2-dichlorobenzene, 1,3-dichlorobenzene and the like; esters such as ethyl acetate, n-propyl acetate, isopropyl acetate, butyl acetate and the like; hydrocarbons such as toluene, xylene, n-hexane, n-heptane, cyclohexane and the like, amides such as dimethylformamide and the like and mixtures thereof.
According to the present invention, 1-(((cyclohexyloxy)carbonyl)oxy)ethyl 2-ethoxy-1-((2'-(1-trityl-1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylate is subjected to deprotection of tetrazole ring protecting group to obtain candesartan cilexetil. The deprotection reaction is carried out in presence of suitable deprotecting agent and solvent. The solvent used is selected from the group comprising of halogenated solvents such as dichloromethane, ethylene dichloride, chloroform, chlorobenzene, chlorotoluene, 1,2-dichlorobenzene, 1,3-dichlorobenzene and the like; alcohol such as methanol, ethanol, propanol and the like; esters such as ethyl acetate, n-propyl acetate, isopropyl acetate, butyl acetate and the like; hydrocarbons such as toluene, xylene, n-hexane, n-heptane, cyclohexane and the like and mixtures thereof. The deprotecting agent used is selected from hydrochloric acid, hydrobromic acid, phosphoric acid and the like.
According to the present invention, the candesartan cilexetil is crystallized from suitable solvent. The solvent used is selected from the group comprising of alcohol such as methanol, ethanol, propanol and the like; esters such as ethyl acetate, n-propyl acetate, isopropyl acetate, butyl acetate and the like and mixtures thereof. The candesartan cilexetil obtained is having solvent and need further drying under suitable conditions in order to qualify for desired residual solvent limits of pharmacopeia standard. The drying method used is selected from the group comprising of vacuum drying, fluidized bed drying, freeze drying, rotary vacuum drying convection drying and the like as known in the literature. The relative humidity is maintained by using method selected from the group comprising of use of de-humidifier, desiccant dryer method and the like. The drying is carried out at temperature from about room temperature to 200?C, for 1-50 h.
The starting material ethyl 1-((2'-cyano-[1,1'-biphenyl]-4-yl)methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylate is prepared according to process known in prior art.
According to the present invention, the substituted tetrazole derivative of Formula I can be optionally converted to pharmaceutically acceptable salts well known in the prior art.
According to the present invention, the substituted tetrazole derivative of Formula I obtained by process of the present invention being essentially free of nitrosamines are shaving nitrosamine impurities well within the specifications prescribed safe for human consumption, preferably nitrosamine impurity is less than 0.01 ppm, wherein the limit of detection is 0.01 ppm.

EXAMPLES
Example 1: Preparation of irbesartan
A round bottomed flask is charged with o-xylene (50 ml), triethyl amine (13 ml) and acetic acid (5.4 ml), subsequently 2-(n-butyl)-3-[[2'-(cyano)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one (10 g) and sodium azide (3.4 g) is added to the flask and the reaction mixture is heated at 120-125°C for 24 h, followed by cooling. The reaction is then quenched by the addition of water (30 ml) . The pH of the aqueous layer is adjusted to about 11 with 30% sodium hydroxide and stirring is done for 10 min, Layers are separated and oily layer is treated with water and xylene. The pH of the aqueous layer is adjusted between 3.5 and 4.5 by the addition of hydrochloric acid and stirring is continued for 1 hour, solid material is formed which is filtered and is washed with water (20 ml) . The solid so obtained is crystallized using methanol and filtered to get irbesartan and is dried using vacuum dryer/rotary vacuum dryer/ fluidized bed dryer with relative humidity of up to 90% by varying temperature from room temperature to 65°C for about 5-35 h.
Nitrosamine impurity: Below detection Limit
Example 2: Preparation of valsartan
(a) Preparation of 2-[(2'-cyano-biphenyl-4-ylmethyl)-pentanoyl-amino]-3-methyl-butyric acid methyl ester
To a solution of 2-[(2'-cyano-biphenyl-4-ylmethyl)-amino]-3-methyl-butyric acid methyl ester hydrochloride (100 g) in water (200 ml) and dichloromethane (200 ml), was added sodium bicarbonate (35 g) at room temperature . The reaction mixture was stirred for 30 minutes. The organic layer was separated and washed with water. The organic layer was dried to control moisture, cooled to 0-10°C and subsequently, valeryl chloride (45 g) and triethylamine (36 g) were added. The reaction mass was then stirred for about 1- 2 h. After the completion of reaction, the reaction mixture was washed with dilute hydrochloric acid. The layers were separated and the organic layer was washed with sodium bicarbonate solution. The solvent from separated organic layer was distilled and the residue was taken in o-xylene. The organic layer containing title compound was treated with hydrochloric solution and subsequently with sodium bicarbonate solution. The resulting organic layer was washed with water and taken as such for next step.

(b) Preparation of 3-methyl-2-{pentanoyl-[2'-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amino}-butyric acid methyl ester
The solvent from solution of product obtained in example 1 in o-xylene was distilled and cooled to room temperature. To the resulting mass added sodium azide (34 g) and tributyl tin azide (170 g). The reaction mixture was then heated to 140°C and stirred for about 22-24 hour. After the completion of reaction, cooled the reaction mixture, which was taken as such for next step.
(c) Preparation of valsartan
To the solution obtained in example 2 was added to sodium hydroxide solution (66 g in 240 ml water) at 0-5 °C. The reaction mixture was then subjected to nitrogen pressure of 2-3 kg/cm2 and stirred for about 35-38 hr. After completion of reaction, separated the layers. The pH of separated aqueous layer was then adjusted to 10.5 using dilute hydrochloric acid and subjected to carbon treatment. The aqueous layer was then subjected to pH adjustment to 2-3 using concentrated hydrochloric acid, treated with dichloromethane and the organic layer was separated. The separated organic layer was distilled under vacuum to residue, which was dissolved in ethyl acetate and the solution was stirred for about 12 hour at room temperature to crystallize valsartan, which was filtered and was slurry washed using dichloromethane and filtered to obtain valsartan, which was dried using vacuum dryer/ fluidized bed dryer/ rotary vacuum dryer with relative humidity of up to 90% by varying temperature from room temperature to 90 °C for about 5-50 h.
Nitrosamine impurity: Below detection Limit

Example 3: Preparation of olmesartan medoxomil
(a) Preparation of trityl olmesartan medoxomil
To a stirred solution of ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(trityl-tetrazol-5-yl)phenyl]phenyl} methylimidazole-5-carboxylate (200 g) in tetrahydrofuran (800 ml) and methanol (0.5 ml), aqueous sodium hydroxide solution is added slowly below 5 °C and continued stirring for about 30 h. After reaction completion, the layers are separated and to the organic layer added potassium carbonate (20 g) and potassium iodide (4.0 g) at about 15 °C. To the reaction mixture, slowly added 4-chloromethyl-5-methyl-1,3-dioxolen-2-one (50 g) and maintained for about 40 h at room temperature. On completion of reaction, the solvent is distilled off and the residue is taken in ethyl acetate (1200 ml) and water (400 ml). The mixture is stirred and layers are separated, the organic layers is chilled and the solid so obtained is filtered and dried to obtain trityl olmesartan medoxomil.
(b) Preparation of olmesartan medoxomil
The trityl olmesartan medoxomil obtained in Example 9 is taken in acetonitrile (200 ml) at room temperature, slowly added dilute hydrochloric acid solution and stirred for about 30 minutes. To the reaction mixture slowly added water (400 ml) at room temperature, cooled the mixture to 0-5 °C and filtered out the solidified triphenylcarbinol. To the filtrate added dichloromethane (300 ml) and adjusted the pH using sodium carbonate solution and washed with water and added acetone (1000 ml) and heat to reflux. The solvent is partially distilled out and cooled the remaining mixture to 0-5 °C, the solid obtained is filtered and crystallized from ethyl acetate. The crystallized solid is filtered to get olmesartan medoxomil, which is dried using vacuum dryer / fluidized bed dryer/rotary vacuum dryer with relative humidity of up to 90% by varying temperature from room temperature to 130 °C for about 5-45 h.
Nitrosamine impurity: Below detection Limit

Example 4: Preparation of losartan potassium
(a) Preparation of 4'-((2-butyl-4-chloro-5-(hydroxymethyl)-1H-imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-carbonitrile
To a solution of 2-butyl-5-chloro-1H-imidazole-4-carbaldehyde (100 g), sodium hydroxide (22.5 g) in water (200 ml) and toluene (500 ml), added 4'-(bromomethyl)-[1,1'-biphenyl]-2-carbonitrile (150 g) and tetra-n-butylammonium bromide (3 g). The resulting mixture is heated to reflux and continued heating for another 30 minutes. The reaction mixture is then cooled to room temperature and the layers are separated, to the water washed organic layer, added methanol (150 ml) and then slowly added sodium borohydride (6 g) and stirred for 2 h. To the reaction mixture added water (500 ml), stirred for 30 minutes and cooled to 0-5 °C. The solid so obtained was filtered to obtain 4'-((2-butyl-4-chloro-5-(hydroxymethyl)-1H-imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-carbonitrile.
(b) Preparation of (1-((2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-2-butyl-4-chloro-1H-imidazol-5-yl)methanol (losartan)
To a solution of treithylamine hydrochloride (145 g) and sodium azide (51 g) in methyl isobutyl ketone (500 ml), added tetra-n-butylammonium bromide (3.5 g) and 4'-((2-butyl-4-chloro-5-(hydroxymethyl)-1H-imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-carbonitrile (100 g). The temperature of reaction mixture is raised to 100-115 °C and maintained for about 30 h. On completion of reaction, the reaction mixture is cooled to 25-30 °C, charged water (300 ml) and 30% sodium hydroxide solution (100 ml), stirred and allowed to settle. The organic layer is separated and is again treated with 5% sodium hydroxide and water (300 ml), stirred, settled and separated the layers. The product from aqueous layer is isolated in presence of ethyl acetate (300 ml) by adjusting the pH to about 3.0 by adding dilute hydrochloric acid at about 10 °C. The solid so obtained is filtered and washed to obtain title compound.

(c) Preparation of losartan potassium
To a solution of (1-((2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-2-butyl-4-chloro-1H-imidazol-5-yl)methanol (losartan) (100 g) obtained above in isopropanol (800ml), added potassium hydroxide (15 g) at room temperature. The reaction mixture is stirred for about 30 minutes and pH of the reaction mixture is adjusted to about 9.5 using potassium hydroxide solution. The reaction mixture is subjected to distillation and about 500 ml of solvent is distilled out. The reaction mixture is then cooled to about 65 °C and n-heptane (100 ml) is added, and stirred for another about 7 h at room temperature. The solid so obtained is filtered and suck dried. The losartan potassium is further dried using vacuum dryer / fluidized bed dryer / rotary vacuum dryer with relative humidity of up to 90% by varying temperature from room temperature to 200°C for about 5-25 h.

Nitrosamine impurity: Below detection Limit

Example 5: Preparation of candesartan cilexetil

(a) Preparation of 1-((2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylic acid

To a mixture of sodium azide (38 g) and water (100 ml), slowly charged tributyl tin chloride (192 g) and stirred for about 4 hour at room temperature. To the reaction mixture was added toluene (500 ml), stirred for 15 minutes and the layers were separated. To the organic layer, charged ethyl 1-((2'-cyano-[1,1'-biphenyl]-4-yl)methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylate (100 g) at room temperature. The temperature of reaction mixture is raised to about 110 ° C, azeotropically removed water and maintained for about 65 h. On completion of reaction, the reaction mixture is cooled to room temperature and added aqueous sodium hydroxide solution (225 ml), stirred for another 15 minutes and allowed to settle. The oily layer was separated and water (300 ml)/methanol (100 ml) was added and the resulting reaction mixture was stirred at 60-65°C for about 3 h. The reaction mixture was then washed with toluene (200 ml) and cooled. To the resulting reaction mixture added ethyl acetate (300 ml) and adjusted the pH to 4-4.5 using dilute hydrochloric acid, the precipitated solid was filtered and dried to obtain title compound.
(b) Preparation of 2-ethoxy-1-((2'-(1-trityl-1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylic acid
To a solution of 1-((2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylic acid (as obtained above)
(100 g) in dichloromethane (500 ml), added triethylamine (63 ml), trityl chloride (76 g). The reaction mixture is stirred for 3 h at room temperature, on completion of reaction, added water (200 ml) and separated the layers. The solvent from organic layer is distilled off and charged methanol (500 ml). The reaction mixture is then cooled to room temperature and maintained for 5-6 h, reduced the temperature to 10-15 °C and stirred for 2 h. The solid so obtained is filtered and dried under vacuum.
(c) Preparation of 1-(((cyclohexyloxy)carbonyl)oxy)ethyl 2-ethoxy-1-((2'-(1-trityl-1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylate
To a solution of 2-ethoxy-1-((2'-(1-trityl-1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylic acid (obtained above) (100 g) in dimethylformamide (200 ml), charged potassium carbonate (25 g)at room temperature and stirred for 10 minutes. To the reaction mixture added cilexetil chloride and raised the temperature of reaction mixture to 60 °C and stirred for 3 h. On completion of reaction, added water (1000 ml) and stirred for about 1.5 h. The solid obtained was filtered and slurry washed with methanol at 10-15 ° C, filtered and dried under vacuum to obtain title compound.
(d) Preparation of 1-(((cyclohexyloxy)carbonyl)oxy)ethyl 1-((2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylate (candesartan cilexetil)
To a solution of 1-(((cyclohexyloxy)carbonyl)oxy)ethyl 2-ethoxy-1-((2'-(1-trityl-1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylate in dichloromethane (400 ml) and methanol (500 ml), slowly added 1N hydrochloric acid, stirred the reaction mixture at room temperature for 2 h. The resulting reaction mixture was washed with water. The layers were separated and the aqueous layer was extracted with dichloromethane (200 ml). The solvent was distilled off and the residue was taken in ethyl acetate and stirred at room temperature for 8 h, the temperature was reduced to 5 °C and stirred for 2 h. The solid obtained was filtered and suck dried to obtain candesartan cilexetil. The candesartan cilexetil is dried using vacuum dryer / fluidized bed dryer / rotary vacuum dryer with relative humidity of up to 90% by varying temperature from room temperature to 150°C for about 5-35 h.

We claim:

1. A process for preparing a substituted tetrazole derivative of formula I essentially free of nitrosamines,

Formula I
wherein R represents an organic residual group, and is selected from linear or branched C1-C6-alkyl or C3-C6-cycloalkyl, each of which is optionally substituted with one or more substituents selected from halogen; hydroxyl; C1-C6-alkyl; C1-C6-alkoxy; and phenyl, pyridine, pyrimidine, imidazole, thiophene and furan, each of which is optionally substituted with one or more substituents selected from the group consisting of C1-C6-alkyl, halogen, hydroxy, nitro and C1-C6-alkoxy, or
R represents phenyl or biphenyl of the following formula:

wherein
each of R1 and R2 is independently selected from the group consisting of
hydrogen; halogen; hydroxy; nitro; C1-C6-alkyl; C3-C6-cycloalkyl; C1-C6-alkoxy; phenylmethyl, pyridylmethyl, pyrimidylmethyl, imidazolylmethyl, benzimidazolylmethyl, thiophenylmethyl and furanylmethyl, each of which is optionally substituted with one to four substituents selected from the group consisting of halogen, carboxy, oxo, C1-C6-alkyl, C1-C6-alkoxy, hydroxy-C1-C6-alkyl, C1-C6-alkoxycarbonyl, C1-C6-alkoxycarbonyl-C1-C6-alkyl, C3-C6-alkanediyl, di(C1-C6-alkyl)aminothiocarbonyl-C1-C6-alkyl, cilexetiloxycarbonyl and medoxomiloxycarbonyl; and amino or amino-C1-C6-alkyl, each of which is optionally substituted with one or two substituents selected from the group consisting of C1-C6-alkyl, C3-C6-cycloalkyl, C1-C6-alkylcarbonyl, carboxy-C1-C6-alkyl and C1-C6-alkoxycarbonyl-C1-C6-alkyl.

wherein the process comprises of drying compound of formula I under controlled humidity drying conditions.

2. The process as claimed in claim 1, wherein the controlled humidity condition is having relative humidity of up to 90%.
3. The process as claimed in claim 1, wherein substituted tetrazole derivatives of Formula I are essentially free of nitrosamines, wherein nitrosamine is less than 0.01 ppm.
4. The process as claimed in claim 1, wherein the substituted tetrazole derivative of Formula I essentially free of nitrosamines is selected from the group comprising wherein R is:

(a) (b) (c)

(d) (e)
in structure (b), R3 represents hydrogen or methyl.
in structure (c), R4 represents hydrogen, methyl, ethyl or cilexetil.
in structure (e), R5 represents hydrogen, methyl, ethyl or medoxomil.

5. The process as claimed in claim 4, wherein the selected substituted tetrazole derivative of Formula I, valsartan, with R = structure (b) and R3 = hydrogen, essentially free of nitrosamines is prepared by steps comprising of:
(a) reacting 2-[(2'-cyano-biphenyl-4-ylmethyl)-amino]-3-methyl-butyric acid methyl ester of Formula IV with valeryl chloride in presence of a base and solvent to obtain 2-[(2'-cyano-biphenyl-4-ylmethyl)-pentanoyl-amino]-3-methyl-butyric acid methyl ester of Formula V;

Formula IV Formula V
(b) reacting 2-[(2'-cyano-biphenyl-4-ylmethyl)-pentanoyl-amino]-3-methyl-butyric acid methyl ester of Formula V with metal azide in presence of trialkyl tin chloride to obtain 3-methyl-2-{pentanoyl-[2'-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amino}-butyric acid methyl ester of Formula VI;

Formula VI
(c) hydrolyzing 3-methyl-2-{pentanoyl-[2'-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amino}-butyric acid methyl ester of Formula VI in presence of a base under pressure, to obtain valsartan; and
(d) drying valsartan under controlled humidity conditions.

6. The process as claimed in claim 5, wherein the base used in step (a) and step (c) is selected from the group comprising of alkali and alkaline earth metal hydroxide, carbonate, bicarbonate, N,N-dimethylamine, N-ethyl-N-methyl amine, triethylamine, diisopropylethylamine, N,N-dimethylbenzylamine, N,N-diethylbenzylamine, N-methyl morpholine, dimethylaminopyridine and pyridine.
7. The process as claimed in claim 5, wherein the solvent used in step (a) is selected from the group comprising of dichloromethane, ethylene dichloride, chloroform, chlorobenzene, chlorotoluene, 1,2-dichlorobenzene, 1,3-dichlorobenzene, ethyl acetate, n-propyl acetate, isopropyl acetate, butyl acetate, toluene, xylene, n-hexane, heptanes, cyclohexane, water and mixtures thereof.
8. The process as claimed in claim 5, wherein the metal azide used in step (b) is selected from the group comprising of lithium azide, sodium azide, potassium azide, calcium azide, magnesium azide and barium azide.
9. The process as claimed in claim 5, wherein the trialkyl tin chloride used in step (b) is selected from the group comprising of trimethyl tin chloride, triethyl tin chloride and tributyl tin chloride.
10. The process as claimed in claim 5, wherein the pressure used in step (c) is between 2 to 6 kg/cm2.